This invention relates to novel benzofuran and dihydrobenzofuran compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
Adrenoreceptors, or adrenergic receptors, are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors. Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure. Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein (HDL) levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridemia, hypercholesterolemia and low HDL levels as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions. Agonists of beta-3 adrenoreceptors are also useful in treating patients with Syndrome X, impaired fasting glucose, and/or impaired glucose tolerance.
Additionally, the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
It has now been found that certain novel benzofuran and dihydrobenzofuran derivatives are effective as beta-3 adrenoreceptor agonists and are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.
The invention specifically relates to benzofuran compounds of Formula I: 
wherein:
--- represents a single or double bond;
R is hydroxy, oxo, halo, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, CF3, NR1R1, SR1, OR1, SO2R2, OCOR2, NR1COR2, COR2, NR1SO2R2, phenyl, or a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N,
each cyclic moiety being optionally substituted with one or more substituents independently selected from hydroxy, R1, halo, cyano, NR1R1, SR1, CF3, OR1, C3-C8 cycloalkyl, NR1COR2, COR2, SO2R2, OCOR2, NR1SO2R2, C1-C10 alkyl, and C1-C10 alkoxy;
R1 is hydrogen or C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from hydroxy, halo, CO2H, CO2(C1-C10 alkyl), C1-C10 alkoxy, and phenyl optionally substituted with CO2H, CO2(C1-C10 alkyl) or C1-C10 alkyl; or
C3-C8 cycloalkyl, phenyl or naphthyl, each optionally substituted with 1 to 4 substituents, and each independently selected from halo, nitro, oxo, C1-C10 alkyl, C1-C10 alkoxy, and C1-C10 alkylthio;
R2 is R1, OR1, NR1R1 or a 5- or 6-membered heterocyclic ring with one or more heteroatoms selected from O, S, and N, said heterocyclic ring being optionally substituted with R1;
Ar is phenyl optionally fused to a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from O, S, and N, wherein the heterocyclic ring in turn is optionally fused to another phenyl ring; or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from N, S, and O, optionally fused to a phenyl ring;
Y is C1-C10 alkyl optionally substituted with 1 to 4 substituents each independently selected from hydroxy, halo, CO2H, CO2(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkylthio, and phenyl optionally substituted with CO2H, CO2(C1-C10alkyl), or C1-C10 alkyl; or
phenyl optionally fused to another phenyl ring or to a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, S, and O; or
a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, S, and O, optionally fused to a phenyl ring;
each cyclic moiety being optionally substituted with one or more substituents independently selected from COR2, halo, NO2, OR1, R1, SR1, NR1R1, (C1-C10 alkyl) OR2, phenyl or tetrazolo;
a is 0, 1, 2, 3, 4, or 5; and
d is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
The terms identified above have the following meaning throughout:
C1-C10 alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
C1-C10 haloalkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms where any Cxe2x80x94C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms. Such groups include trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, fluoroethylenyl, 6-chlorohexyl, and the like.
The term C1-C10 alkoxy means C1-C10 alkyl radicals as defined above bonded through an oxygen (xe2x80x94Oxe2x80x94) linkage. Such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term C1-C10 alkylthio means C1-C10 alkyl radicals as defined above bonded through a sulfur (xe2x80x94Sxe2x80x94) linkage. Such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
C3-C8 cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms. Such groups include cyclopropyl, cyclopentyl, cyclohexyl, and the like.
Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
Each of R2, Ar, and Y includes any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms, with the point of attachment being at any available position on the heterocyclic ring. Where there is more than one heteroatom in a single cyclic group, each heteroatom may be chosen independently of any other heteroatom, in each occurrence. These moieties include, but are not limited to, such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, oxadiazolyl, thiadiazolyl, furazanyl, tetrazolyl, and the like. Such moieties also include, but are not limited to, such 6-membered heterocyclic rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl, triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and the like.
Each of Ar and Y also includes phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms, with the point of attachment being any at available position on the phenyl ring. These moieties include, but are not limited to, such phenyl fused 5-membered heterocyclic groups as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl, benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl, benzothiadiazolyl, benzopyrazolinyl, and the like. Such moieties also include, but are not limited to, such phenyl fused 6-membered heterocyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
Ar also includes phenyl fused to any 5- or 6-membered heterocyclic ring to form a bicyclic moiety as described above, which is further fused on the heterocyclic ring to a second phenyl ring, forming a tricyclic system, with the point of attachment to the core structure of the compound of Formula I being at any available position of the first phenyl ring. These include, but are not limited to, such groups as carbazolyl, carbazolinyl, acridinyl, xanthenyl, phenoxathiinyl, phenoxazinyl, phenanthridinyl, dibenzofuryl, dibenzopyranyl, dibenzodioxanoyl, phenazinyl, thianthrenyl and the like.
Ar also includes any 5 or 6-membered saturated or unsaturated heterocyclic ring having any combination of one or more N, S, or O atoms, which is further fused to a phenyl ring, with the point of attachment to the core molecule of Formula I being at any available position on the heterocyclic ring. These include, but are not limited to, such phenyl-fused with 5-membered hetero-bicyclic moieties as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indoyl, indazolyl, indolizinyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl, benzopyrazolinyl, and the like. It also includes such phenyl-fused with 6-membered hetero-bicyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
When any moiety is described as being substituted, it may have one or more of the indicated substituents that may be located at any available position on the moiety. When there are two or more substituents on any moiety, each term may be defined independently of any other in each occurrence. For example, NR1R1 may represent NH2, NHCH3, N(CH3)CH2CH2CH3, and the like.
Examples of the compound of Formula I, which are illustrative of the present invention, but not limiting in any way, are listed in Table 1.
In one embodiment of the present invention, compounds of Formula I are those wherein Y is phenyl or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, each cyclic moiety being optionally substituted with one or more substituents selected from COR2, halo, and C1-C10 alkyl.
In another embodiment, compounds of Formula I are those wherein a is 0, 1, or 2; Ar is phenyl, a 5- or 6-membered heterocycle containing one heteroatom, or phenyl fused to a 5- or 6-membered heterocycle; d is 1; and Y is phenyl substituted with COR2; and R2 is OR1.
Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and the like.
Base salts include, for example, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with, for example, such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides, and iodides; aralkyl halides like benzyl and phenethyl bromides, and the like.
The esters in the present invention are non-toxic, pharmaceutically acceptable esters such as, for example, alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters. Additional esters such as, for example, phenyl-C1-C5 alkyl or C1-C5 alkyl-Oxe2x80x94C(xe2x80x94O)-C1-C5alkyl may be used, as well as methyl ester. The compound of Formula I may be esterified by a variety of conventional procedures including, for example, reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride may be reacted with the alcohol in the presence of an acylation catalyst such as, for example, 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as, for example, dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide, or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally an acylation catalyst. Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride, and optionally pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as, for example, 4-DMAP or pyridine.
Sensitive or reactive groups on the compound of Formula I may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols.
The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any asymmetric center may be in the (R)-, (S)- or (R,S) configuration, preferably in the (R)- or (S)-configuration, whichever is most active. The compounds of Formula I where the side chain containing the (R)axe2x80x94Arxe2x80x94 moiety with the hydroxy component above the plane as depicted in Formula I are preferred.
All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (xe2x95x90Zxe2x80x94) or trans (xe2x95x90Exe2x80x94) form, and are encompassed within the scope of this invention.
The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific Ar and Y moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. For example, after preparation of a compound according to Reaction Scheme 1, in order to enable purification of the end product by, for instance, flash chromatography, compounds of Formula I wherein R1 is H, may be selectively protected, for example, as a carbamate derivative obtained by, for example, treatment with a reagent such as di-tert-butyl dicarbonate or other means known in the art. After purification, the carbamate group may easily be removed by treatment with an acid such as HCl or trifluoroacetic acid by means known in the art.
In the Reaction Schemes below, one skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. When specific reagents or solvents are shown in a Reaction Scheme, therefore, they are meant to be illustrative examples of specific, but not limiting, conditions for the execution of that particular Reaction Scheme.
General Methods of Preparation of Formula I Compounds
In general, Formula I compounds may be prepared by standard techniques known in the art and by known processes analogous thereto. In particular, three such standard methods may be used, the selection of which may be based, among other considerations, upon the commercial availability of the required individual starting materials. These three methods are illustrated in Reaction Schemes 1, 2, and 3 described below.
The compounds of Formula I where each variable may be any moiety within that variable""s definition may be synthesized according to Reaction Scheme 1 by coupling an appropriate epoxide 1 with an appropriate amine 2. The epoxide of Formula 1 is either commercially available, known in the art (see, e.g., WO98/32475), or may be readily prepared from known hydroxy compounds as exemplified in Reaction Scheme 6. Preparation of 2 is described in Reaction Schemes 12 and 13 below. The reaction of Reaction Scheme 1 is typically carried out in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at a temperature of from about xe2x88x9210xc2x0 C. to reflux. 
Alternatively, Formula I compounds where each variable may be any moiety within that variables definition except that dxe2x88x921, may be prepared by a reductive amination as shown in Reaction Scheme 2. Reaction of an aldehyde of Formula 4 (preparation described below in Reaction Scheme 8) with an amino alcohol of Formula 3 (preparation described below in Reaction Scheme 7) followed by subsequent reduction gives the desired transformation. 
A third general route to Formula I compounds where each variable may be any moiety within that variable""s definition except that dxe2x88x921, is shown in Reaction Scheme 3. An amino alcohol 3 (Reaction Scheme 7) and a carboxylic acid 5 (preparation described in Reaction Schemes 9 and 10) are coupled to provide an amide of Formula 6. Reduction of the Formula 6 amides with an appropriate reagent such as borane-dimethylsulfide complex provides the Formula I compounds. 
Compounds of Formula I where Y is a halogen, prepared by the above described methods, may in turn be used to prepare other compounds of Formula I where Y is any alkenyl, cycloalkenyl, phenyl, or a 5- or 6-membered heterocyclic ring. Methods for accomplishing this inter-conversion are described below in Reaction Schemes 4 and 5. For example, a compound of Formula I, wherein Y is bromo, may be prepared by Reaction Scheme 1 using corresponding starting materials 2 or 4, where Y is bromo, each of which may, in turn, be prepared by Reaction Schemes 9, 10, 12, or 14. The resulting Formula I compound is then protected by standard methods to give a compound of Formula 7a, (Yxe2x95x90Br) as shown in Reaction Scheme 4. The compound of Formula 7a is then converted to the boronic ester 8, which is then subjected to a Suzuki coupling reaction with a halo-Y compound of Formula 9, in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle, to provide the corresponding Formula 7 compounds. Deprotection of Formula 7 compounds by acid or fluoride-catalyzed hydrolysis provides the corresponding Formula I compounds. 
The coupling may also be performed in the reverse manner, that is, a boronic ester derivative 10, prepared from a halophenyl compound 9a, may be added to the iodo compound of Formula 7b, as shown in Reaction Scheme 5, to give Formula Ib compounds. 
The salts and esters of the Formula I compounds of the invention may be readily prepared by conventional chemical processes well known in the art.
General Method of Preparation of Intermediates
The starting materials required to carry out the above described reactions (e.g., epoxides 1, amines 2, amino alcohols 3, aldehydes 4, and carboxylic acids 5) are in many cases commercially available or may be readily prepared by methods known to those skilled in the art. The following routes are exemplary of such methods, but are not intended to be limiting in any way.
The epoxides 1 of Reaction Scheme 1 are commercially available or may be prepared according to one of the many procedures described in the literature known to those skilled in the art (see, e.g., WO 99/32475) from starting materials which are either commercially available or known in the art. One such general method for the preparation of Formula 1 epoxides is illustrated in Reaction Scheme 6, in which a substituted aryl or heteroaryl hydroxy compound of Formula 11, such as, for example, a phenol, hydroxypyridine, hydroxybenzofuran, hydroxyindole, hydroxyquinoline, and the like, is allowed to react with a glycidyl-, alkyl-, or arylsulfonate of Formula 12 in the presence of a strong base such as, for example, sodium hydride. The alkyl or aryl sulfonate used in this reaction may be racemic or an enantiomerically pure compound, such as (2S)-(+)- or (2R)-(xe2x88x92)-glycidyl tosylate, both of which are commercially available. 
The amino alcohols 3 are either commercially available, known in the art, or may be prepared by ring opening of the epoxides 1 with a nitrogen nucleophile, such as, for example, dibenzylamine or phthalimide, in presence of a base. Removal of the phthalimide by cleavage with hydrazine or the benzyl groups by hydrogenolysis provides the desired amino alcohol of Formula 3. An example of this is shown in Reaction Scheme 7. 
Synthesis of aldehyde starting materials of Formula 4 may be accomplished by oxidation of alcohols of formula 14, for example, under Swern conditions as shown in Reaction Scheme 8. 
Compounds of Formula I where --- represents double bond may be prepared from corresponding intermediates in which --- represents a double bond. Examples of intermediates where --- represents a double bond are, for example, benzofuran acids of Formula 5a, benzofuran esters of 17a, and benzofuran alcohols of formula 14a. Utilizing a known benzofuran synthesis (Yoo et al., Bioorg. Med. Chem. 5:445, 1997), benzofuran esters 17a may be prepared from commercially available benzaldehydes, and hydrolyzed to 5a or reduced to 14a as shown in Reaction Scheme 9. 
Likewise, compounds of Formula I where --- represents a single bond may be prepared from intermediates where --- represents a single bond. For example, dihydrobenzofuran esters of formula 17b, may be prepared from the intermediate 16 by reduction, halogen substitution, and cyclization as shown in Reaction Scheme 10. The corresponding dihydrobenzofuran acids of Formula 5b may be obtained hydrolysis of the Formula 17b esters. Reduction of 17b gives the dihydrobenzofuran alcohol of Formula 14b. 
In the case of either Reaction Scheme 9 or 10, if Y is a halogen atom, the alcohol products 14a or 14b may be protected as compounds of Formula 20 and used to prepare a variety of other Formula 14 alcohols where Y is other than halogen. This is exemplified in Reaction Scheme 11 for the preparation of compounds of Formula 14, where Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle. Conversion of 20a to the corresponding benzofuran or dihydrobenzofuran boronic ester of Formula 21, followed by Suzuki coupling of 21 with a halo-Y compound of Formula 9 yields, after hydrolysis, the Formula 14 alcohols. 
The amine starting materials of Formula 2 in which dxe2x88x921 are generally available by standard methods involving conversion of a carboxylic acid 5 to an amide of Formula 22 and reduction with borane. This sequence is shown in Reaction Scheme 12 for Formula 2 amines wherein dxe2x88x921. 
Formula 2 amines in which d is 2 may be prepared by standard homologation sequences of known intermediates where d=1. For example, aldehydes of Formula 4 can undergo an alkyl chain extension according to well known procedures such as that described by Wittig et al., (Chem. Ber., 2514, 1962), and the process may be repeated in order to prepare the acetic and propionic acid homologues of Formula 5. These chain-extended acids may be used in place of the acid of Formula 5 by a method analogous to Reaction Scheme 12, to provide a variety of Formula 2 amines in which d=2.
Formula 2 amines in which Y is other than hydrogen or halo may be prepared by palladium-catalyzed coupling reactions on the N-protected amine of Formula 23a, followed by deprotection, as shown in Reaction Scheme 13. Formula 2 amines prepared in this way in which the Y group is substituted by an acid, ester, alcohol, ketone, sulfide, or nitro group can also provide additional Formula 2 amines by manipulation of that functional group by directed hydrolysis, esterification, reduction, oxidation, and/or reduction reactions, and the like. 
Dihydrobenzofuran alcohols of Formula 14b, where --- represents a single bond and Y is a halogen, carboxylic acid, or ester may be prepared from Formula 20b compounds where Y is hydrogen, via halogenation, for example, iodination, carbonylation, and deprotection steps, as exemplified in Reaction Scheme 14. 
Compounds of Formula 14 where Y is an alkenoic or alkanoic acid or ester may be prepared from Formula 20 compounds (protected forms of Formula 14a or 14b), where Y is halogen. An example of this sequence involves palladium-catalyzed coupling of 20a with an Palkenoic acid derivative, as shown in Reaction Scheme 15. Reduction of the double bond in the product 20d provides compound of Formula 20e. Deprotection of 20d and 20e provides the corresponding Formula 14 alcohols which are converted to Formula I compounds as described above. 
Alcohol intermediates of Formula 14 in which Y is other than hydrogen or halo may also be prepared from the bromo alcohols, 14a or 14b (Yxe2x95x90Br), as shown in Reaction Scheme 16, by a procedure analogous to the previously described Suzuki coupling methodology of Reaction Schemes 4, 11, and 13. This may be accomplished either directly, or via a 4-step sequence involving protection of the Formula 14a or 14b (Yxe2x95x90Br) alcohol, for example, as a t-butyldimethylsilyl ether 20f, conversion of this compound to a boronic ester, and Suzuki coupling reaction of the boronic ester with a halo-Y compound of Formula 2 compound to 20g, and finally deprotection to 14. 
The halo-Y compounds of Formula 9 where halo is iodo, chloro, or bromo and Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle, used in Reaction Schemes 4, 11, 13, and 16, are either commercially available or synthesized by standard methods known to those skilled in the art. One such standard method is direct halogenation of a known Hxe2x80x94Y compound with a halogenating agent; other methods include the functional group conversion of HOxe2x80x94Y, NH2xe2x80x94Y compounds to halo-Y compounds by standard substitution methods. A particular illustration is the preparation of halo-Y compounds of Formula 9b and 9c where Y represents an oxazole or a thiazole, prepared by direct halogenation of the unsubstituted compound 24, or by diazotization of a NH2xe2x80x94Y compound 26 as shown in Reaction Scheme 17. 
The heterocyclic intermediates, 24 and 25, used to prepare 9b and 9c are accessible by standard methods from acyclic materials, for example, by the reactions as shown in Reaction Schemes 18, 19, and 20. 
Using a combination of the above Reaction Schemes, a wide variety of compounds of Formula I may be prepared. Further illustration of these methods are in the specific Examples described hereinbelow. These examples are not intended nor should they be construed to limit the invention in any way.
When the following abbreviations are used herein, they have the following meaning:
General Experimental Procedures
HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mmxc3x9723 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile, and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
1H NMR spectra were determined at 300 MHz using a General Electric GE-OMEGA 300 spectrometer. Chemical shifts are reported in parts per million (xcex4) values relative to tetramethylsilane as internal standard. Spin multiplicities are reported using the following abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br) Coupling constants are in Hertz.
Melting points were recorded in open capillary tubes and are uncorrected.